Compounds that stimulate glucose utilization and methods of use

ABSTRACT

The invention provides novel compounds of the Formula (I) that stimulate rates of glucose oxidation in myocardial cells: 
     
       
         
         
             
             
         
       
         
         
           
             wherein W, Cyc, p, Y, X, Z, R, R 1 , R 2 , R 3 , R 4 , I, m and n are as defined for Formula (I) herein. The invention also relates to pharmaceutical compositions comprising compounds capable of stimulation of glucose oxidation, methods for increasing glucose oxidation rates in myocardial cells, and methods of treatment of myocardial ischemia.

This patent application is a continuation-in-part of U.S. Ser. No.10/313,990, filed Dec. 5, 2002, which is a continuation-in-part of U.S.Ser. No. 10/181,274 which is a United States National filing under 35U.S.C. 371 which is based on PCT/IB02/02525, filed Apr. 1, 2002, nowwithdrawn, the entirety of the disclosure of each of these applicationswhich is hereby incorporated into the present application by reference.

FIELD OF THE INVENTION

The invention relates to novel compounds that stimulate rates of glucoseoxidation in myocardial cells. The invention also relates topharmaceutical compositions comprising compounds capable of stimulatingglucose oxidation, methods for increasing glucose oxidation rates inmyocardial cells, and methods of treatment of myocardial ischemia.

BACKGROUND OF THE INVENTION

Myocardial ischemia is a common clinical pathology that occurs in thesetting of angina pectoris, acute myocardial infarction, or duringcardiac surgery. Myocardial ischemia is a major clinical problem, withits complications being the major cause of mortality and morbidity inWestern society.

It has been reported that stimulating glucose oxidation both during andfollowing ischemia can benefit the ischemic heart. Br J Pharmacol 128:197-205, 1999, Am J Physiol 275: H1533-41, 1998. Biochimica etBiophysica Acta 1225: 191-9, 1994, Pediatric Research 34: 735-41, 1993,Journal of Biological Chemistry 270: 17513-20, 1995. Biochimica etBiophysica Acta 1301: 67-75, 1996, Am J Cardiol 80: 11A-16A, 1997,Molecular & Cellular Biochemistry 88: 175-9, 1989, Circ Res 65: 378-87,1989, Circ Res 66: 546-53, 1990, American Journal of Physiology 259:H1079-85, 1990, American Journal of Physiology 261: H1053-9, 1991, Am JPhysiol Heart Circ Physiol 280: H1762-9., 2001, J Am Coll Cardiol 36:1378-85., 2000.

To meet the high energy demands of the contracting muscle, the heartmust produce a constant and plentiful supply of the free energy carrier,adenosine triphosphate (ATP). This energy is produced by the metabolismof a variety of carbon substrates, including carbohydrates such asglucose. The metabolism of fatty acid is the other major source ofenergy for the heart.

Glucose metabolism in the heart consists of two important pathways,namely glycolysis and glucose oxidation.

It has been shown that during ischemia (such as that produced by anginapectoris, myocardial infarction or heart surgery) the levels ofcirculating fatty acids in the plasma can be dramatically elevated. AmHeart J 128: 61-7, 1994. As a result, during ischemia and reperfusionthe heart is exposed to high levels of fatty acids, which results in thepreferential use of fatty acids as an oxidative substrate over glucose.It further has been reported that this over-reliance on fatty acids as amajor source of ATP contributes to fatty acid-induced ischemic damage.This observation has sparked numerous approaches directed at switchingsubstrate utilization back to glucose in an attempt to protect the heartfrom fatty acid-induced ischemic damage. J Cardiovasc Pharmacol 31:336-44., 1998, Am Heart J 134: 841-55., 1997, Am Physiol 273: H2170-7.,1997, Cardiovasc Drugs Ther 14: 615-23., 2000, Cardiovasc Res 39:381-92., 1998, Am Heart J 139: S115-9., 2000, Coron Artery Dis 12:S8-11., 2001, Am J Cardiol 82: 14K-17K., 1998, Molecular & CellularBiochemistry 172: 137-47, 1997, Circulation 95: 313-5., 1997, GenPharmacol 30: 639-45., 1998, Am J Cardiol 82: 42K-49K., 1998, CoronArtery Dis 12: S29-33., 2001, Coron Artery Dis 12: S3-7., 2001, J NuclMed 38: 1515-21., 1997. Current approaches that are used to manipulatemyocardial energy metabolism involve either stimulating glucosemetabolism directly or indirectly (i.e., inhibiting fatty acidmetabolism).

Since high fatty acid oxidation rates markedly decrease glucoseoxidation, one approach to increasing glucose oxidation is to inhibitfatty acid oxidation. This has proven effective both during andfollowing ischemia, and this pharmacological approach is starting to seeclinical use. Although a number of pharmacological agents designed toinhibit fatty acid oxidation have recently been developed, the direct1-oxidation inhibitor, trimetazidine, was the first anti-anginal agentwidely used that has a mechanism of action that can be attributed to anoptimization of energy metabolism Circulation Research. 86: 580-8, 2000.

Trimetazidine is reported to primarily act by inhibiting fatty acidoxidation, thereby stimulating glucose oxidation in the heart.

A second clinically effective agent that is reported to switch energymetabolism from fatty acid to glucose oxidation is ranolazine. It hasbeen reported that this agent stimulates glucose oxidation secondary toan inhibition of fatty acid oxidation Circulation 93: 135-42., 1996.

The detrimental effects of fatty acids on mechanical function during andfollowing ischemia may also be attenuated by agents that increaseglucose oxidation directly. Numerous experimental studies have reportedthat stimulation of glucose oxidation by using dichloroacetate (DCA)following ischemia (at the expense of fatty acids) can benefit theischemic heart. Am Heart J 134: 841-55, 1997. Although DCA is aneffective compound designed to stimulate glucose oxidation, it has ashort biological half-life.

Therefore, there is need to develop novel class of compounds and toidentify compounds that can stimulate glucose oxidation, have longbiological life, and be effective in treatment or prevention ofmyocardial ischemia

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to novel compoundsrepresented by Formula (I):

wherein

-   (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,    optionally substituted aralkyl or optionally substituted aralkenyl;-   (b) CyC is C₃ or C₄ cycloalkyl;-   (c) p is an integer from 0 to 4;-   (d) m is 1 or 2;-   (e) Y is O, S, or NR;-   (f) if m is 1 and if p is 0, Y is O, and n is not 0, then Z is    (cyclo)alkycarbonyl or if m is 1 and if p is 0, Y is O and n is 0,    then Z is heterocycle alkyl;-   (g) X is O, S, NR, or CR³R⁴;-   (h) R is H, alkyl, aryl, or

-   -   where i is an integer from 2 to 4;

-   (i) Z is H, alkyl, heterocycle alkyl, cycloalkyl, aryl or optionally    substituted C₁-C₆ alkylcarbonyl or

when X is NR and R is

or when X is NR, R and Z may be taken together with N to form anitrogen-containing heterocyclic ring;

-   (j) R¹ is H, alkyl or aryl;-   (k) R² is H, alkyl, aryl or ═O;-   (l) R³ and R⁴ are, independently, H, alkyl or aryl; or when X is    CR³R⁴ then R³ and R⁴, taken together with the carbon atom, may form    a heterocyclic ring; and-   (m) n is an integer from 1 to 10; or a pharmaceutically acceptable    salt, ester or prodrug thereof.

In one alternate preferred aspect, the present invention is directed tonovel compounds which are represented by Formula (IIS):

wherein (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,optionally substituted aralkyl or optionally substituted aralkenyl; (b)Cyc is C₃ or C₄ cycloalkyl; and (c) p is an integer from 1 to 4, or apharmaceutically acceptable salt, ester or prodrug thereof. While notwishing to be bound by any particular mechanism of action, it isbelieved that compounds of Formula (IIS) are esterfied with CoA in vivo.

According to one embodiment, novel compounds are provided which arerepresented by Formula (IIIa):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

According to an alternate embodiment, provided are novel compoundsrepresented by Formula (IIIb):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl or aryl;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

In a further embodiment, provided are novel compounds represented byFormula (IIIc):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is O, S, or NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

Another embodiment provides compounds represented by Formula (IIId):

wherein

W is C₁-C₆ alkyl, halogen or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an interger for 0 to 3 when Cyc is C₄ cycloalkyl or p is aninterger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is C;

X is NR;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

An additional embodiment is directed to novel compounds represented byFormula (IIIe):

wherein

W is aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is 1;

Y is O, S, or NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

According to one aspect, the present invention is further directed tomethods for increasing or improving glucose utilization in myocardial orother types of cells, tissue or organs of warm blooded animals,especially those which are capable of high glucose metabolism (e.g.,heart and other muscles). The method comprises treating cells, tissue ororgans with substituted or unsubstituted cyclopropane carboxylic acid orcyclobutane carbothioic acid represented by the Formula (IIS):

wherein W, Cyc and p are as defined in connection with Formula (IIS), ora cyclopropane carboxylic acid or cyclobutane carboxylic derivative ofFormula (I) or any of Formulas (IIIa) to (IIIe).

According to an alternate aspect, the present invention is also directedto pharmaceutical compositions comprising a compound according toFormula (IIS), Formula (I) or any of Formulas (IIIa) to (IIIe) andsuitable pharmaceutical carriers, excipients or fillers.

According to a further aspect, the present invention is directed to amethod of treating physiological conditions or disorders that may beeffectively treated by increasing of cell glucose utilization. Accordingto one embodiment, such method comprises administering to a patient inneed of such treatment an effective amount of a pharmaceuticalcomposition comprising substituted or unsubstituted cyclopropanecarboxylic acid or cyclobutane carbothioic acid according to Formula(IIS) or a cyclopropane carboxylic acid or cyclobutane carboxylic acidderivative of Formula (I) and any of Formulas (IIIa) to (IIIe).

The present invention is further directed to kits including apharmaceutical composition according to the present invention.

The methods of the present invention are applicable for treating warmblooded animal subjects, such as mammals, including humans, primates,etc.

Additional embodiments will be apparent from the Detailed Descriptionand from the claims.

DEFINITIONS

In accordance with the present invention and as used herein, thefollowing terms are defined to have following meanings, unlessexplicitly stated otherwise:

The term “alkenyl” refers to unsaturated aliphatic groups having atleast one double bond.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic (including cycloalkyl andpolycyclic alkyl) groups.

The terms “alkoxy” and “alkoxyl” refer to a group having the formula,R—O—, wherein R is an alkyl group.

The term “alkoxycarbonyl” refers to —C(O)OR wherein R is alkyl.

The term “aralkenyl” refers to an alkenyl group substituted with an arylgroup. Preferably the alkenyl group has from 2 to about 6 carbon atoms.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Suitable aralkyl groups include benzyl, phenethyl, and the like,all of which may be optionally substituted. Preferably the alkyl grouphas from 1 to about 6 carbon atoms.

The term “aryl” refers to an aromatic group which has at least one ringhaving a conjugated pi electron system and includes a carbocyclic aryl,heterocyclic aryl and biaryl groups, all of which may be optionallysubstituted.

The term “aryloxy” refers to a group having the formula, R—O—, wherein Ris an aryl group.

The term “aralkoxy” refers to a group having the formula, R—O—, whereinR is an aralkyl group.

“Biaryl” refers to phenyl substituted by carbocyclic or heterocyclicaryl as defined herein, ortho, meta or para to the point of attachmentof the phenyl ring.

“Brine” refers to an aqueous saturated solution of sodium chloride.

“Carbocyclic aryl” refers to aromatic groups wherein the ring atoms onthe aromatic ring are carbon atoms. Carbocyclic aryl groups includemonocyclic carbocyclic aryl groups and naphthyl groups, all of which maybe optionally substituted. Suitable carbocyclic aryl groups includephenyl and naphthyl. Suitable substituted carbocyclic aryl groupsinclude indene and phenyl substituted by one to two substituents suchbeing advantageously lower alkyl, hydroxy, lower alkoxy, loweralkoxycarbonyl, halogen, trifluoromethyl, difluoromethyl, nitro, andcyano. Substituted naphthyl refers to naphthyl, more preferably 1- or2-naphthyl, substituted by Y1, Y2 and/or Y3 as defined in connectionwith formula (I) hereinabove.

“Cycloalkenyl” refers to a cyclic alkenyl group. Suitable cycloalkenylgroups include, for example, cyclopentenyl and cyclohexenyl.

“Cycloalkyl” refers to a cyclic alkyl group having at least one ring andincludes polycyclic groups, including fused ring cyclic alkyl groups andbridged cycloalkyl groups. Suitable cycloalkyl groups include, forexample, cyclohexyl, cyclopropyl, cyclopentyl, cycloheptyl andadamantyl.

“Cyclohexylmethyl” refers to a cyclohexyl group attached to CH₂.

“Diol” refers to chemical species having at least two hydroxy (—OH)functional groups. Diols may contain more than two hydroxy groups.“Vicinal diols” are those in which two hydroxy groups are on adjacentcarbons, as found for example in pinanediol.

“Fused carbocyclic” refers to a multicyclic fused carbocyclic ringhaving both aromatic and non-aromatic rings. Suitable fused carbocyclicrings include fluorenyl, tetralin and the like.

“Fused carbocyclic alkyl” refers to an alkyl group substituted with afused carbocyclic ring moiety, preferably a multicyclic fusedcarbocyclic ring including both aromatic and non-aromatic rings.Suitable fused carbocyclic alkyl groups include fluorenylmethyl, and thelike.

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

“Heteroaralkenyl” refers to an alkenyl group substituted with aheteroaryl, and includes those heterocyclic systems described in“Handbook of Chemistry and Physics”, 49th edition, 1968, R. C. Weast,editor; The Chemical Rubber Co., Cleveland, Ohio. See particularlySection C, Rules for Naming Organic Compounds, B. FundamentalHeterocyclic Systems. Preferably the alkenyl group has from 2 to about 6carbon atoms.

“Heteroaralkyl” refers to an alkyl group substituted with a heteroaryl,such as picolyl, and includes those heterocyclic systems described in“Handbook of Chemistry and Physics”, 49th edition, 1968, R. C. Weast,editor; The Chemical Rubber Co., Cleveland, Ohio. See particularlySection C, Rules for Naming Organic Compounds, B. FundamentalHeterocyclic Systems. Preferably the alkyl group has from 1 to about 6carbon atoms.

“Heteroaryl” refers to aromatic groups having from 1 to 14 carbon atomsand the remainder of the ring atoms are heteroatoms, and includes thoseheterocyclic systems described in “Handbook of Chemistry and Physics”,49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co.,Cleveland, Ohio. See particularly Section C, Rules for Naming OrganicCompounds, B. Fundamental Heterocyclic Systems. Suitable heteroatomsinclude oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, andsuitable heterocyclic aryls include furanyl, thienyl, pyridyl, pyrrolyl,pyrimidyl, pyrazinyl, imidazolyl, and the like.

“Heterocycle” or “Heterocyclic” refers to both heteroaryl andheterocyclo groups.

“Heterocycle alkyl” refers to an alkyl group substituted with aheterocycle group.

“Heterocyclicoxy” refers to the group —OR where R is a heterocyclegroup.

“Heterocyclo” refers to a reduced heterocyclic ring system comprised ofcarbon, nitrogen, oxygen and/or sulfur atoms, and includes thoseheterocyclic systems described in “Handbook of Chemistry and Physics”,49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co.,Cleveland, Ohio. See particularly Section C, Rules for Naming OrganicCompounds, B. Fundamental Heterocyclic Systems.

“Heterocycloalkyl” refers to an alkyl group substituted with aheterocyclo group, and includes those heterocyclic systems described in“Handbook of Chemistry and Physics”, 49th edition, 1968, R. C. Weast,editor; The Chemical Rubber Co., Cleveland, Ohio. See particularlySection C, Rules for Naming Organic Compounds, B. FundamentalHeterocyclic Systems. Preferably the alkyl group has from about 1 toabout 6 carbon atoms.

The term “lower” referred to herein in connection with organic radicalsor groups defines such radicals or groups with one and up to andincluding 5 carbon atoms, preferably up to and including 4 carbon atoms,and advantageously one or two carbon atoms. Such radicals or groups maybe straight chain or branched chain.

“Pharmaceutically acceptable salt” includes salts of the compounds ofthe present invention derived from the combination of such compounds andan organic or inorganic acid. In practice the use of the salt formamounts to use of the base form. The compounds of the present inventionare useful in both free base and salt form, with both forms beingconsidered as being within the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which depicts glucose oxidation in an isolatedperfused working rat heart model at the indicated concentrations ofcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester(MM054) as compared to a control.

FIG. 2 is a graph which depicts glucose oxidation in an isolatedperfused working rat heart model at the indicated concentrations ofcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester(MM056) as compared to a control.

FIG. 3 is a graph which depicts glucose oxidation in an isolatedperfused working rat heart model at increasing concentrations ofcyclopropanecarboxylic acid, 2-isopropoxy-ethyl ester (MM070) ascompared to a control.

FIG. 4 is a graph which depicts glucose oxidation in an isolatedperfused working rat heart model at increasing concentrations ofcyclopropanecarboxylic acid (MM001) as compared to a control.

FIG. 5 is a graph which depicts glucose oxidation in an isolatedperfused working heart model at the indicated concentrations ofdichloroacetate (DCA), Compound 15 (MM068), Compound 41 (MM094) andCompound 45 (MM098), compared to a control.

FIG. 6 is a graph which depicts glucose oxidation in an isolatedperfused rat heart model at the indicated concentrations of DCA,cyclopropanecarboxylic acid (MM001) and cyclobutanecarboxylic acid(MM013) as compared to a control.

FIG. 7 is a graph which depicts glucose oxidation in an isolatedperfused rat heart model for concentrations of cyclopropanecarboxylicacid (MM001) as compared with a control.

FIG. 8 is a graph which depicts glucose oxidation in an isolatedperfused rat heart model for increasing concentrations ofcyclobutanecarboxylic acid (MM013) as compared to a control.

FIG. 9 is a graph which depicts Pyruvate Dehydrogenase Kinase (PDHK)activity at 1 mM of DCA or cyclopropanecarboxylic acid (MM001) as apercent of a control, using the PDHK assay described in Example C.

FIG. 10 is a graph which depicts PDHK activity at 1 mM of DCA,cyclopropanecarboxylic acid (MM001) or the CoA ester ofcyclopropanecarboxylic acid (MM053) as a percent of a control, using thePDHK assay described in Example C.

FIG. 11 depicts a schematic for a mechanism of intracellular activationof cyclopropanecarboxylic acid (MM001) to give the corresponding CoAester (MM053).

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to the use of certaincompounds in methods of treatment which increase glucose utilization andwhich ameliorate conditions which would benefit from increased glucoseutilization. Included are methods for increasing glucose utilization ina cell, tissue, or organ of a warm blooded animal comprising treatingsaid cell, tissue or organ with a glucose utilization increasingeffective amount of at least one compound represented by the formulasset forth herein. Also included are methods for treatment ofphysiological conditions or disorders treatable by increasing glucoseutilization comprising administering to a patient in need of suchtreatment, an effective amount to increase glucose utilization of apharmaceutical composition comprising at least one compound as describedherein. Such compounds include the compounds represented by Formulas(I), (IIS), III and (IIIa) to (IIIe).

While not wanting to be bound by any particular mechanism of action, wehave observed that compounds having activity as inhibitors of PyruvateDehydrogenase Kinase (PDHK) demonstrate beneficial activity instimulating glucose oxidation. Using methods that directly measureenergy metabolism in a working heart model we screened compoundsdescribed herein (such as those depicted in Tables 1, 2A and 2B andMM001 and MM013) for their ability to stimulate glucose oxidation.Structures and molecular weights for MM001 and MM013 are depicted below.

Molecular Weight MM001

86.09 MM013

100.12

As a positive control we used DCA at a concentration of 3 mM. We wereable to identify compounds that stimulated glucose oxidation at 100 μM.We subsequently performed concentration curves in order to determine thepotency of these compounds. Data are shown in FIG. 6:

This approach was used to test the efficacy of the compounds describedherein at stimulating glucose oxidation in the intact heart. MM001 iscyclopropanecarboxylic acid, which we had identified as a stimulator ofglucose oxidation in the heart. MM013 is a compound that we demonstratedto stimulate glucose oxidation.

Concentration curves for MM001 and MM013 are shown in FIG. 7 and FIG. 8,respectively.

In order to determine if the activity in stimulating glucose oxidationwere, indeed, associated with activity in the inhibition of PDHK, wesubjected a compound (MM001) that we had identified as having glucoseoxidation stimulating activity to an in vitro PDHK assay. PDHK activitywas measured as described in Example C:

Our initial results demonstrated that the compound tested did notdirectly inhibit PDHK in vitro. However, we had evidence to prove thatPDHK activity in ex vivo hearts was inhibited (FIG. 9).

It is believed that the compounds described herein act by a prodrugmechanism in inhibiting PDHK, that is, when administered in vivo thecompound undergoes an intracellular modification to produce a productthat inhibits PDHK. (See FIG. 11) Thus, it is believed that thecompounds described herein act as prodrugs. To demonstrate this, wemodified one of the compounds (MM001) in a manner in which it isbelieved to be modified intracellularly. This compound (MM053) isdepicted below.

When tested in the in vitro PDHK assay, MM053 was active and did inhibitPDHK activity.

Molecular Weight MM053

835.61

Thus, MM053 appears to be an active form of the compound (MM001) thatinhibits PDHK directly (See FIG. 10). It is believed that the compoundsdescribed herein that stimulate glucose oxidation may be similarlymodified in vivo and may be prodrugs of the corresponding CoA esters.

According to one aspect, compounds of the Formula (III) which are activein stimulating glucose oxidation are provided. In particular, thecompounds represented by Formula (III) are:

wherein

W is C₁-C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is O, S, or NR;

X is O, S, NR, or CR³R⁴;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

X is NR and R is

R is H, alkyl, aryl or

where i is an integer from 2 to 4;

R¹ is H, alkyl, or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

Certain compounds of Formula (III) are represented by Formulas (IIIa) to(IIIe).

According to one aspect, the present invention provides novel compoundswhich are derivatives of a cyclopropane carboxylic acid or a cyclobutanecarboxylic acid. These compounds exhibit glucose oxidation stimulatingactivity in myocardial cells and other types of cells. The compoundsaccording to the present invention are represented by the Formula (I):

wherein

-   (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,    optionally substituted aralkyl or optionally substituted aralkenyl;-   (b) Cyc is C₃ or C₄ cycloalkyl;-   (c) p is an integer from 0 to 4;-   (d) m is 1 or 2;-   (e) Y is O, S, or NR;-   (f) if m is 1 and if p is 0, Y is O, and n is not 0, then Z is    (cyclo)alkycarbonyl or if m is 1 and if p is 0, Y is O and n is 0,    then Z is heterocycle alkyl;-   (g) X is O, S, NR, or CR³R⁴;-   (h) R is H, alkyl, aryl, or

-   -   where i is an integer from 2 to 4;

-   (i) Z is H, alkyl, heterocycle alkyl, cycloalkyl, aryl or optionally    substituted C₁-C₆ alkylcarbonyl or

when X is NR and R is

or when X is NR, R and Z may be taken together with N to form anitrogen-containing heterocyclic ring;

-   (j) R¹ is H, alkyl or aryl;-   (k) R² is H, alkyl, aryl or ═O;-   (l) R³ and R⁴ are, independently, H, alkyl or aryl; or when X is    CR³R then R³ and R⁴, taken together with the carbon atom, may form a    heterocyclic ring; and-   (m) n is an integer from 1 to 10; or a pharmaceutically acceptable    salt, ester or prodrug thereof.

According to an alternate aspect, the present invention provides novelcompounds according to the present invention which are represented byFormula (IIS):

wherein (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,optionally substituted aralkyl or optionally substituted aralkenyl; (b)Cyc is C₃ or C₄ cycloalkyl; and (c) p is an integer from 1 to 4; or apharmaceutically acceptable salt, ester or prodrug thereof.

According to one embodiment, novel compounds are provided which arerepresented by Formula (IIIa):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

According to an alternate embodiment, provided are novel compoundsrepresented by Formula (IIIb):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl or aryl;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

In a further embodiment, provided are novel compounds represented byFormula (IIIc):

wherein

W is C₁-C₆ alkyl, halogen, or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is O, S, or NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

Another embodiment provides compounds represented by

Formula (IIId):

wherein

W is C₁-C₆ alkyl, halogen or aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is an interger for 0 to 3 when Cyc is C₄ cycloalkyl or p is aninterger from 0 to 2 when Cyc is C₃ cycloalkyl;

Y is O;

X is NR;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

An additional embodiment is directed to novel compounds represented byFormula (IIIe):

wherein

W is aryl;

Cyc is C₃ or C₄ cycloalkyl;

p is 1;

Y is O, S, or NR;

X is O, S, NR, or CR³R⁴;

R is H, alkyl, aryl, or

where i is an integer from 2 to 4;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or

if X is NR and R is

R¹ is H, alkyl or aryl;

R² is H, alkyl, aryl or ═O;

R³ and R⁴ are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.

Certain compounds according to the present invention may be convenientlyprepared from the appropriate substituted or unsubstituted cyclopropanecarbonyl chloride or cyclobutane carbonyl chloride according to thefollowing reaction scheme:

wherein W, Cyc, and p are as defined in connection with Formula (I), Yis O such that R′YH is an alcohol and

R′ is

where R¹, R², X, and n are as defined in connection with Formula (I) andZ is H, alkyl (including cycloalkyl), aryl or alkycarbonyl.

Other compounds of Formula (I) and of Formulas (IIIa) to (IIIe),including those depicted in Tables 1A, 2A and 2B, may be prepared bymethods similar to those described in Examples 1 to 27 and using theappropriate starting materials.

Suitable solvents include inert organic solvents such as dichloromethaneand suitable base catalysts include triethylamine and pyridine.

Reaction conditions may be varied depending on the starting materialsand the desired end product. Optimization of the reaction conditionswould be apparent for one of ordinary skill.

The invention further provides a method for increasing the rate ofglucose oxidation and improving glucose utilization in myocardial andother cells, tissue or organs of humans and animals. It has beendiscovered that certain substituted cyclopropanecarbothioic acid andcyclobutanecarbothioic acid derivatives and certain substituted orunsubstituted cyclopropanecarboxylic acid and cyclobutanecarboxylic acidderivatives represented by Formula (IIS), by Formula (I) and any ofFormula (IIIa) to (IIIe) can increase glucose utilization in myocardialan other types of cells, tissue or organs of warm blooded animals,including humans.

Compounds of Formula (IIS) have the structure:

wherein

W is C₁-C₆ alkyl, halogen, optionally substituted aryl, optionallysubstituted aralkyl or optionally substituted aralkenyl; Cyc is C₃ or C₄cycloalkyl; and p is an integer from 1 to 4; or a pharmaceuticallyacceptable salt, ester or prodrug thereof.

According to one embodiment, the method according to the presentinvention comprises treating cells, tissue or organs of an animal withat least one compound represented by Formula (I), any of Formulas (IIIa)to (IIIe) or Formula (IIS) in an amount effective to stimulate glucoseutilization. The compounds of Formula (I), Formulas (IIIa) to (IIIe) orFormula (IIS) may be delivered to the cells, tissues or organs byconventional means of administrating pharmaceutical compositions such asoral administration, injection or infusion, etc., of the compounds ofthe Formula (I), Formulas (IIIa) to (IIIe) or (IIS) to the animal.

The invention further provides pharmaceutical compositions comprising,as its active component, at least one compound according to the Formulas(I), (IIIa) to (IIIe) or (IIS) or their pharmaceutically acceptablesalts, esters or prodrugs. Pharmaceutical compositions comprising morethan one compound according to the Formulas (I), (IIIa) to (IIIe) or(IIS), their various mixtures and combinations are also contemplated tobe within the scope of the present invention.

Pharmaceutical compositions or formulations include compositions andformulations conventionally used in the pharmaceutical arts and maycomprise carriers and excipients compatible with oral, intravenous,intramuscular, intraarterial, intracranial, and/or intracavityadministration. Suitable pharmaceutical compositions and/or formulationsmay further compose colloidal dispersion systems, or lipid formulations(e.g., cationic or anionic lipids), micelles, microbeads, etc.

As noted, pharmaceutical compositions of the present invention maycomprise pharmaceutically acceptable and physiologically acceptablecarriers, diluents or excipients. Examples of suitable carriers,diluents and excipients include solvents (aqueous or non-aqueous),solutions, emulsions, dispersion media, coatings, isotonic andabsorption promoting or delaying agents, compatible with pharmaceuticaladministration, and other commonly used carriers known in the art.

Pharmaceutical compositions may also include carriers to protect thecomposition against rapid degradation or elimination from the body, and,thus may comprise a controlled release formulation, including implantsand microencapsulated delivery systems. For example, a time delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed.

Pharmaceutical compositions can be formulated to be compatible with aparticular route of administration. For oral administration, acomposition can be incorporated with excipients and used in the form oftablets, pills or capsules, e.g., gelatin capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included inoral formulations. The tablets, pills, capsules, etc., can contain anyof the following ingredients, or similar compounds: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; or a flavoring orsweetening agent.

Pharmaceutical compositions for parenteral, intradermal, or subcutaneousadministration can include a sterile diluent, such as water, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose.

Pharmaceutical compositions for injection include sterile aqueoussolutions (where water-soluble) or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL™ (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). Antibacterial andantifungal agents include, for example, parabens, chlorobutanol, phenol,ascorbic acid and thimerosal. Isotonic agents, for example, sugars,polyalcohols such as manitol, sorbitol, sodium chloride may be includedin the composition. Including an agent which delays absorption, forexample, aluminum monostearate and gelatin can prolong absorption ofinjectable compositions.

The pharmaceutical formulations can be packaged in dosage unit form forease of administration and uniformity of dosage. Dosage unit form asused herein refers to physically discrete units suited as unitarydosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the pharmaceuticalcarrier or excipient.

The compositions can be administered by any route compatible with adesired outcome. Thus, routes of administration include oral (e.g.,ingestion or inhalation), intraperitoneal, intradermal, subcutaneous,intravenous, intraarterial, intracavity, intracranial, and parenteral.The compositions can also be administered using implants andmicroencapsulated delivery systems.

Compositions, including pharmaceutical formulations can further includeparticles or a polymeric substance, such as polyesters, polyamine acids,hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide/glycolidecopolymers, polylactide/glycolide copolymers, or ethylenevinylacetatecopolymers. Cyclopropanecarboxylic acid, cyclopropanecarboxylic acid andderivatives and modified forms thereof can be entrapped inmicrocapsules, for example, by the use of hydroxymethylcellulose orgelatin-microcapsules, or poly (methylmethacrolate) microcapsules,respectively, or in a colloid drug delivery system.

In instances where cell, tissue or organ targeting is desired, acomposition of the invention can of course be delivered to the targetcell, organ or tissue by injection or infusion or the like. Targetingcan be achieved by injection or infusion in practicing the methods ofthe invention. Targeting can also be achieved by using proteins thatbind to a cell surface protein (e.g., receptor or matrix protein)present on the cell or population of cell types. For example, antibodiesor antibody fragments (e.g., Fab region) that bind to a cell surfaceprotein can be included in the delivery systems in order to facilitatecell, tissue or organ targeting. Viral coat proteins that bindparticular cell surface proteins can be used for targeting. For example,naturally occurring or synthetic (e.g. recombinant) retroviral envelopeproteins with known cell surface protein binding specificity can beemployed in the liposomes in order to intracytoplasmically delivercyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivativesand modified forms thereof into target cells, tissue or organs. Thus,delivery vehicles, including colloidal dispersion systems, can be madeto have a protein coat in order to facilitate targeting orintracytoplasmic delivery of cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and derivatives and modified forms thereof.

The invention further provides a method for prophylactic and therapeutictreatments of various physiological condition or disorder treatable byincreasing or improving glucose utilization in cells, tissue or organsof a patient by administering to the patient in need of such treatment,effective amounts of pharmaceutical compositions comprising substitutedor unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylicacid and cyclobutanecarboxylic acid derivative compounds represented bythe Formulas (I), (IIIa) to (IIIe) and (IIS).

Disorders or conditions that can be treated with a method according tothe present invention include, for example, ischemic/reperfusion injury,post myocardial infarction, angina, heart failure, a cardiomyopathy,peripheral vascular disease, diabetes, and lactic acidosis, or symptomsor side effects associated with heart surgery (e.g., open heart surgery,bypass surgery, heart transplant).

The method according to the present invention includes administering apharmaceutical compositions comprising effective amounts of substitutedor unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylicacid and cyclobutanecarboxylic acid derivative compounds represented bythe Formulas (I), (IIIa) to (IIIe) and (IIS) in a single daily dose, orthe total daily dosage may be administered in divided doses severaltimes daily. Furthermore, the pharmaceutical compositions may beadministered as a single dose or over a period of time.

Patients that can be treated with the method according to the presentinvention include all known kind of mammals, including non humanprimates (apes, gibbons, chimpanzees, orangutans, macaques), companionanimals (dogs and cats), farm animals (horses, cows, goats, sheep,pigs), experimental animals (mouse, rat, rabbit, guinea pig), andhumans.

The dosage regiment utilizing the pharmaceutical compositions accordingto the present invention is selected based on various factors such astype of physiological condition to be treated, age, weight, sex of thepatient, severity of the conditions to be treated, the route ofadministration, and particular compound contained in the pharmaceuticalcomposition. A physician or veterinarian of ordinary skill can readilydetermine and prescribed the effective amount of the pharmaceuticalcomposition to prevent or to treat the specific physiological condition.

The daily dosage may be varied over wide range and can be such that theamount of an active compound selected from a substitutedcyclopropanecarbothioic acid or cyclobutanecarbothioic acid, or asubstituted or an unsubstituted cyclopropanecarboxylic acid orcyclobutanecarboxylic acid derivative compound represented by any ofFormulas (I), (IIS) and (IIIa) to (IIIe) is sufficient to increaseglucose utilization in a cell, tissue or organ of a warm blooded animaland to achieve the desired effect of alleviating or preventing fattyacid-induced ischemic damage.

The invention provides kits containing substituted or unsubstitutedcyclopropanecarboxylic acid or cyclobutanecarboxylic acid,cyclopropanecarboxylic acid or cyclobutanecarboxylic acid, substitutedcyclopropanecarbothioic acid or cyclobutanecarbothioic acid andderivatives and modified forms thereof represented by the Formulas (I),(IIIa) to (IIIe) and Formula (IIS), including pharmaceuticalformulations, packaged into a suitable set. A kit typically includes alabel or packaging insert including instructions for use, in vitro, invivo, or ex vivo, of the components therein.

The term “packaging material” refers to a physical structure housing thecomponents of the kit, such as cyclopropanecarboxylic acid,cyclopropanecarboxylic acid or derivatives or modified forms thereof.The packaging material can maintain the components sterilely, and can bemade of material commonly used for such purposes (e.g., paper,corrugated fiber, glass, plastic, foil, ampules, etc.). The label orpackaging insert can include appropriate written instructions, forexample, practicing a method of the invention.

Kits of the invention therefore can additionally include instructionsfor using the kit components in a method of the invention. Instructionscan include instructions for practicing any of the methods of theinvention described herein. Thus, for example, a kit can include acyclopropanecarboxylic acid, cyclopropanecarboxylic acid or a derivativeor modified form thereof in a pharmaceutical formulation in a container,pack, or dispenser together with instructions for administration to ahuman subject. Instructions may additionally include indications of asatisfactory clinical endpoint or any adverse symptoms that may occur,or any additional information required by the Food and DrugAdministration for use in humans.

A kit may include instructions for increasing or improving glucoseutilization in vitro, ex vivo or in vivo. In other embodiments, a kitincludes instructions for treating a disorder associated with deficientor inefficient glucose utilization. In one aspect, the instructionscomprise instructions for treating a subject having or at risk of havingischemic/reperfusion injury, post myocardial infarction, angina, heartfailure, a cardiomyopathy, peripheral vascular disease, diabetes, orlactic acidosis. In another aspect, the instructions compriseinstructions for treating a subject having or at risk of having heartsurgery (e.g., open heart surgery, bypass surgery, heart transplant andangioplasty).

The instructions may be on “printed matter,” e.g., on paper or cardboardwithin the kit, or on a label affixed to the kit or packaging material,or attached to a vial or tube containing a component of the kit.Instructions may additionally be included on a computer readable medium,such as a disk (floppy diskette or hard disk), optical CD such as CD- orDVD-ROM/RAM, magnetic tape, electronic storage media such as RAM and ROMand hybrids of these such as magnetic/optical storage media.

Kits can additionally include a buffering agent, a preservative, or astabilizing agent. Each component of the kit can be enclosed within anindividual container and all of the various containers can be within asingle package.

The present invention is further illustrated in the following exampleswherein all parts, percentages, and ratios are in equivalents, alltemperatures are in ° C., and all pressures are atmospheric unlessotherwise indicated:

EXAMPLES Example 1 Preparation of Cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester

Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml) andtriethylamine (1.1 eq, 5.26 mmol, 0.73 ml) were taken in a 10 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5g, 0.43 ml) was added in a dropwise fashion maintaining the temperatureat 0° C. with constant stirring.

A yellowish-orange solid was observed after some time.

Stirring was continued for 1 hour at 0° C. The reaction was monitored bythin layer chromatography, and then quenched with saturated ammoniumchloride solution. The mixture was then transferred to a separatoryfunnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloricacid (2×5 ml) and then with brine (5 ml). The dichloromethane layer wasseparated from the aqueous layer, dried over anhydrous sodium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellow liquid. Purification was by flash chromatography and vacuumdistillation (b.p.=144° C., 3.0 mm of Hg) which afforded the pureproduct as a colorless liquid (527.0 mg, 48%).

The compound obtained was characterized by ¹H and ¹³C NMR, IR, and massspectroscopy:

¹H NMR (300 MHz, CDCl₃) δ 4.2 (m, 2H), 3.68 (m, 2H), 3.64 (m, 6H), 3.52(m, 2H), 3.36 (s, 3H), 1.62 (m, 1H), 0.99 (m, 2H), 0.84 (m, 2H); IR(CHCl₃) 2876.07, 1726.62, 1199.53, 1179.49, 1107.97 cm⁻¹; ¹³C NMR (75.5MHz, CDCI₃) δ 174.67, 71.80, 70.44, 69.06, 63.45, 58.84, 12.65, 8.35; MS(ES, MNa⁺): calculated for C₁₁H₂₀O₅Na 255.11, found 255.1.

Example 2 Preparation of Cyclobutanoylglycine(Cyclobutanecarbonyl-amino)-acetic acid)

Methyl ester glycine hydrochloride (1 eq, 2.39 mmol, 300 mg) andpyridine (2 eq, 4.78 mmol, 0.39 ml) were suspended in (5 ml) ofdichloromethane followed by addition of DMAP (1.5 eq, 218.5 mg) in oneportion; the reaction mixture was stirred for 30 minutes at roomtemperature. After 30 minutes, cyclobutanecarbonyl chloride (2 eq, 4.77mmol, 0.54 ml) was added slowly and the reaction mixture was stirred for4 hours at room temperature. The solvent was evaporated in vacuo and theresidue extracted with ethyl acetate. The ethyl acetate layer was driedand concentrated to dryness. The crude material obtained was purified byflash chromatography to yield pure compound A (358 mg, 87%).

To a solution of A in (6 ml) THF, was added lithium hydroxide (1.1 eq,2.3 mmol, 2.3 ml, 1M) at room temperature and the reaction mixture wasstirred for 1.5 hours. The reaction mixture was then concentrated invacuo and acidified to pH=3 with 2N HCl. The crude product was thenextracted with ethyl acetate and purified by recrystallization, using anethyl acetate/hexane mixture. The product obtained afterrecrystallization was further purified by flash chromatography and againrecrystallization to give the title compound B as a white solid (196 mg,59%).

The compound obtained was characterized by ¹H and ¹³C NMR, IR, and massspectroscopy:

¹HNMR (300 MHz, CD₃OD) δ 3.87 (s, 2H), 3.14 (quintet, 1H), 1.84-2.2 (m,6H); IR (USCOPE) 3313.01, 3098.14, 2986.18, 2940.41, 2525.15, 2469.13,2435.25, 1738.49, 1620.96, 1566.87, 1486.61, 1346.65, 1264.23 cm⁻¹; ¹³CNMR (75.5 MHz, CD₃OD) δ 178.20, 173.12, 41.69, 40.61, 26.12, 19.01; HRMS(ES, MNa⁺) calculated for C₇H₁₁NO₃Na 180.06311, found 180.06290.

Example 3 Preparation of Cyclobutanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester

Triethylene glycol monomethyl ether (1.1 eq, 4.64 mmol, 0.74 ml) andtriethylamine (1.1 eq, 4.64 mmol, 0.65 ml) were taken in a 25 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclobutanecarbonyl chloride (4.22 mmol, 0.5 g,0.48 ml) was added in a dropwise fashion maintaining the temperature at0° C. with constant stirring (vigorous reaction).

A pink colored solution was observed after some time. An extra 4 ml ofdichoromethane was added to maintain proper stirring (the reactionmixture became thick). Stirring was continued for 1 hour at 0° C. Thereaction was monitored by thin layer chromatography and then quenchedwith saturated ammonium chloride solution. The mixture was thentransferred to a separatory funnel, washed with 5% sodium bicarbonate(2×5 ml), 1:1 hydrochloric acid (2×5 ml) and then with brine (5 ml). Thedichloromethane layer was separated from the aqueous layer, dried overanhydrous sodium sulphate, filtered, and evaporated in vacuo to give thetitle product as a pale yellowish-pink liquid. The liquid was purifiedby flash chromatography and vacuum distillation (b.p.=189° C., 3.0 mm ofHg) to yield the pure product as a colorless liquid (679.6 mg, 65.34%).

The product was characterized by ¹H and ¹³C NMR, IR and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 4.18 (m, 2H), 3.4 (m, 2H), 3.6 (m, 6H), 3.5 (m,2H), 3.32 (s, 3H), 3.1 (quintet, 1H), 2.2 (m, 4H), 1.86 (m, 2H); IR(CDCI₃) 2946.38, 2870.68, 1730.73, 1179.35, 1109.59 cm⁻¹; ¹³C NMR (75.5MHz, CDCI₃) δ 175.45, 71.93, 70.58, 69.21, 63.40, 59.01, 38.0, 25.24,18.38; MS (ES, MNa⁺): calculated for C₁₂H₂₂O₅Na 269.13, found 269.1.

Examples 4, 6 to 14, 18 and 19 General Procedure for the Preparation ofCertain Cyclopropanecarboxylic Acid and Cyclobutanecarboxylic AcidDerivatives

where W, Cyc, and p are as defined for Formula (I) and Y is O such thatR′—YH is an alcohol, where R′ is:

where R¹, R², X, and n are defined in connection with Formula (I) and Zis H, alkyl (including cycloalkyl), aryl or alkylcarbonyl. Suitablebases include triethylamine or pyridine. Suitable solvents includedichloromethane or other inert organic solvents.

Following the procedures described in Example 1 and Example 3 and usingthe appropriate starting alcohol and cycloalkyl cyclopropane carboxylicacid chloride materials, (the appropriate starting alcohols were used inplace of triethylene glycol monomethyl ether), the notedcyclopropanecarboxylic acid and of cyclobutanecarboxylic acidderivatives respectively were prepared (see Table I). The compoundsprepared, cycloalkyl carbonylchloride and alcohol starting materialsused for their preparation and their molecular weights are summarized inTable 1.

The compounds were characterized by ¹H NMR, ¹³C NMR, IR and massspectroscopy.

Example 5 Preparation of Cyclopropanoylalanine

The procedure of Example 2 was followed except that 2.5 equivalents ofpyridine was used instead of 2 equivalents, cyclopropanecarbonylchloride was used in place of cyclobutanecarbonylchloride and methylester alanine hydrochloride was used in place of methyl ester glycinehydrochloride.

Purified compound B (321 mg, 87%) was characterized by ¹H and ¹³C NMR,IR, and mass spectroscopy.

¹HNMR (300 MHz, CD₃OD) δ 8.25 (br s, 1H), 4.38 (m, 1H), 3.25 (s, 1H),1.64 (m, 1H), 1.39 (dd, 3H), 0.7-0.9 (m, 4H); IR (USCOPE) 3323.78,3020.25, 2645.76, 1791.56, 1729.13, 1632.33, 1537.27, 1406.24, 1281.02cm⁻¹; ¹³C NMR (75.5 MHz, CD₃ OD) δ 176.28, 176.18, 49.38, 17.77, 14.59,7.41, 7.33; HRMS (ES, M): calculated for C₇H₁₂NO₃ 158.08117, found158.08123.

Example 15 Preparation of Cyclopropanecarboxylic acid 2-ethoxy-ethylester

2-Ethoxy-ethanol (1.1 eq, 5.26 mmol, 0.47 g, 0.51 ml) and pyridine (1.1eq, 5.26 mmol, 0.42 g, 0.43 ml) were taken in a 25 ml round bottom flaskand dichloromethane (6 ml) was added. This mixture was cooled to 0° C.and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) wasadded in a dropwise fashion maintaining the temperature at 0° C. withconstant stirring.

An orange-yellow colored solution was observed after sometime. Stirringwas continued for 1 hour at 0° C. The reaction was monitored by thinlayer chromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel,washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5ml), and then with brine (5 ml). The dichloromethane layer was separatedfrom the aqueous layer, dried over anhydrous magnesium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellowish-orange liquid. Purification was by flash chromatography andvacuum distillation (b.p.=43° C., 2.8 mm of Hg) which afforded the pureproduct as a colorless liquid (515.8 mg, 55.4%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

1HNMR (400 MHz, CDCl₃) δ 4.22 (m, 2H), 3.62 (m, 2H), 3.53 (q, 2H), 1.64(m, 1H), 1.2 (t, 3H), 0.98 (m, 2H), 0.84 (m, 2H); MS (ES, M+Na):calculated for C₈H₁₄O₃Na 181.19, found 181.1; IR (CH₂Cl₂) 2976.37,2869.55, 1728.78, 1455.55, 1177.86 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ174.76, 68.39, 66.60, 63.73, 15.17, 12.91, 8.62.

Example 16 Preparation of Cyclobutanecarboxylic acid 2-ethoxy-ethylester

2-Ethoxy-ethanol (1.1 eq, 4.64 mmol, 0.42 g, 0.45 ml) and triethylamine(1.1 eq, 4.64 mmol, 0.47 g, 0.65 ml) were taken in a 25 ml round bottomflask and dichloromethane (6 ml) was added. This mixture was cooled to0° C. and then cyclobutanecarbonyl chloride (4.22 mmol, 0.5 g, 0.48 ml)was added in a dropwise fashion maintaining the temperature at 0° C.with constant stirring.

An orange-yellow colored solution was observed after sometime. Stirringwas continued for 1 hour at 0° C. The reaction was monitored by thinlayer chromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel,washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5ml), and then with brine (5 ml). The dichloromethane layer was separatedfrom the aqueous layer, dried over anhydrous magnesium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellow liquid. Purification was attempted by flash chromatography andvacuum distillation (b.p.=48° C., 2.8 mm of Hg) which afforded the pureproduct as a colorless liquid (421.3 mg, 57.7%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (500 MHz, CDCl₃) δ 4.18 (m, 2H), 3.58 (m, 2H), 3.48 (q, 2H), 3.14(m, 1H) 2.2 (m, 4H), 1.9 (m, 2H), 1.17 (t, 3H); MS (ES, M+Na):calculated for C₉H₁₆O₃Na 195.11, found 195.1; IR (CH₂Cl₂) 2976.99,2949.17, 1732.12, 1444.39, 1175.39 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ175.33, 68.38, 66.58, 63.51, 38.06, 25.32, 18.47, 15.16.

Example 17 Preparation of cyclopropanecarboxylic acid 2-isopropoxy-ethylester

2-Isopropoxy-ethanol (1.1 eq, 5.26 mmol 0.55 g, 0.61 ml) and pyridine(1.1 eq, 5.26 mmol, 0.42 g, 0.43 ml) were taken in a 25 ml round bottomflask and dichloromethane (6 ml) was added. This mixture was cooled to0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml)was added in a dropwise fashion maintaining the temperature at 0° C.with constant stirring.

An orange-yellow colored solution was observed after sometime. An extra2 ml of dichoromethane was added to maintain proper stirring (reactionmixture becomes thick). Stirring was continued for 1 hour at 0° C. Thereaction was monitored by thin layer chromatography and then quenchedwith saturated ammonium chloride solution. The mixture was thentransferred to a separatory funnel, washed with 5% sodium bicarbonate(2×5 ml), 1:1 hydrochloric acid (2×5 ml), and then with brine (5 ml).The dichloromethane layer was separated from the aqueous layer, driedover anhydrous magnesium sulphate, filtered, and evaporated in vacuo togive the title product as a pale yellowish-orange liquid. Purificationwas by flash chromatography and vacuum distillation (b.p.=33° C., 2.9 mmof Hg) which afforded the pure product as a colorless liquid (630.2 mg,76.40%).

Characterization of the resulting compound was done by ¹H and ¹³C NMR,IR, and mass spectroscopy:

¹HNMR (400 MHz, CDCl₃) δ 4.2 (m, 2H), 3.6 (m, 3H), 1.65 (m, 1H), 1.15(d, 6H), 1.0 (m, 2H), 0.85 (m, 2H); IR (CH₂Cl₂) 3015.93, 2972.88,1729.05, 1454.97, 1177.85 cm⁻¹; ¹³C NMR (125 MHz, CDCI₃) δ 174.72,71.93, 65.95, 64.0, 22.06, 12.92, 8.54; MS (ES, MNa⁺): calculated forC₉H₁₆O₃Na 195.09, found 195.0

Example 20 Preparation of Cyclobutanecarboxylic Acid,2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester

Diethylene glycol (0.5 eq, 1 mmol, 0.11 g) and pyridine (2.2 eq, 2.2mmol, 0.174 g, 0.18 ml) were taken in a 10 ml round bottom flask anddichloromethane (4 ml) was added. This mixture was cooled to 0° C. andthen cyclobutanecarbonyl chloride (2.0 mmol, 0.24 g, 0.23 ml) was addedin a dropwise fashion maintaining the temperature at 0° C. with constantstirring.

A white thick suspension was observed after sometime.

Stirring was continued for 1 hour at 0° C. The reaction was monitored bythin layer chromatography and then quenched with saturated ammoniumchloride solution. The mixture was then transferred to a separatoryfunnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloricacid (2×5 ml), and then with brine (5 ml). The dichloromethane layer wasseparated from the aqueous layer, dried over anhydrous magnesiumsulphate, filtered, and evaporated in vacuo to give the title product asa pale yellowish liquid. Purification was by flash chromatography andvacuum distillation (b.p.=113° C., 2.8 mm of Hg) which afforded the pureproduct as a colorless liquid (130.0 mg, 46.42%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (500 MHz, CDCl₃) δ 4.2 (m, 4H), 3.63 (m, 4H), 3.14 (m, 2H),1.9-2.2 (m, 12H); MS (ES, M+Na): calculated for C₁₄H₂₂O₅Na 293.15, found293.0; IR (CH₂Cl₂) 2949.36, 2869.67, 1731.42, 1445.39, 1174.72 cm⁻¹;¹³CNMR (125 MHz, CDCl₃) δ 175.26, 69.16, 63.32, 63.27, 38.05, 25.33,18.49.

Example 21 Preparation of Cyclopropanecarboxylic acid,2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester

Triethylene glycol (1.6 mmol, 0.24 g) and pyridine (2.2 eq, 3.52 mmol,0.28 g, 0.28 ml) were taken in a 10 ml round bottom flask anddichloromethane (5 ml) was added. This mixture was cooled to 0° C. andthen cyclopropanecarbonyl chloride (3.4 mmol, 0.36 g, 0.31 ml) was addedin a dropwise fashion maintaining the temperature at 0° C. with constantstirring.

A white, thick suspension was observed after sometime. Stirring wascontinued for 1 hour at 0° C. The reaction was monitored by thin layerchromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel,washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5ml), and then with brine (5 ml). The dichloromethane layer was separatedfrom the aqueous layer, dried over anhydrous magnesium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellowish liquid. Purification was by flash chromatography and vacuumdistillation (b.p.=127° C., 2.8 mm of Hg) which afforded the pureproduct as a colorless liquid (234.5 mg, 50.97%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (500 MHz, CDCl₃) δ 4.2 (m, 4H), 3.68 (m, 4H), 3.64 (br s, 4H),1.62 (m, 2H), 0.97 (m, 4H), 0.84 (m, 4H); MS (ES, M+Na): calculated forC₁₄H₂₂O₆Na 309.14, found 309.0; IR(CH₂Cl₂) 3015.01, 2951.60, 2873.12,1726.69, 1454.28, 1177.84 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ 175.0, 70.0,69.0, 63.0, 13.0, 8.0.

Example 22 Preparation of Cyclobutanecarboxylic acid,2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester

The procedure described in Example 21 was followed using the followingamounts of these reagents: triethylene glycol (1.6 mmol, 0.24 g),pyridine (2.2 eq, 3.52 mmol, 0.28 g, 0.28 ml); and cyclobutanecarbonylchloride (3.4 mmol, 0.40 g, 0.39 ml).

The compound was characterized by NMR (¹H and ¹³C), IR and massspectroscopy:

¹HNMR (500 MHz, CDCl₃) δ 4.2 (m, 4H), 3.68 (m, 4H), 3.62 (br s, 4H),3.14 (m, 2H), 2.1-2.3 (m, 8H), 1.8-2.0 (m, 4H); MS (ES, M+Na):calculated for C₁₆H₂₆O₆Na 337.14, found 337.0; IR (CH₂Cl₂) 2948.71,2869.27, 1731.17, 1445.80, 1175.60 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ175.29, 70.59, 69.27, 63.39, 38.06, 25.33, 18.49.

Example 23 Preparation of Cyclopropanecarboxylic acid2-[{2-[bis(2-cyclopropanecarbonyloxy-ethyl)-amino]-ethyl}-(2-cyclopropanecarbonyloxy-ethyl)-amino]ethylester

A solution of the diamine tetra-ol (1 eq, 4.23 mmol, 1.0 g), pyridine(1.0 eq, 4.23 mmol, 0.33 g, 0.34 ml) and triethylamine (5.0 eq, 0.021mol, 2.12 g, 2.90 ml) was taken in a 25 ml round bottom flask andtoluene (10 ml) was added. This mixture was cooled to 0° C. and thencyclopropanecarbonyl chloride (0.019 mol, 1.98 g, 1.72 ml) was added inone shot with vigorous stirring, maintaining the temperature at 0° C.

A yellowish-white thick suspension was observed after sometime. Stirringwas continued for 15 minutes at 0° C. The reaction was monitored by thinlayer chromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel, andextracted with ethyl acetate (2×25 ml). The ethyl acetate layer waswashed with brine (1×20 ml), dried over anhydrous magnesium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellowish liquid. Purification was by flash chromatography whichafforded the pure product as a colorless liquid (900.0 mg, 42.0%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 4.13 (t, 8H), 3.3 (m, 3H), 2.82 (t, 8H), 2.68(s, 4H) 1.64 (m, 4H), 0.88 (m, 16H); MS (ES, M+H): calculated forC₂₆H₄₀N₂O₈+H 509.29, found 509.0; IR (CH₂Cl₂) 3014.69, 2958.19, 2826.89,1725.90, 1452.31, 1173.00 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ 174.59, 62.62,53.55, 53.29, 12.92, 8.50.

Example 24 Preparation of Cyclopropanecarboxylic Acid(2-isopropoxy-ethyl)-amide

A solution of the amino ether (1.1 eq, 5.26 mmol, 0.54 g, 0.64 ml),pyridine (0.5 eq, 2.39 mmol, 0.19 g, 0.19 ml), triethylamine (1.1 eq,5.26 mmol, 0.53 g, 0.73 ml) was taken in a 10 ml round bottom flask anddichloromethane (6 ml) was added. This mixture was cooled to 0° C. andthen cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) was addedin a dropwise fashion, maintaining the temperature at 0° C.

A white precipitate was observed after sometime. Stirring was continuedfor 30 minutes at 0° C. The reaction was monitored by thin layerchromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel,washed with water (1×10 ml), brine (2×10 ml), dried over anhydrousmagnesium sulphate, filtered, and evaporated in vacuo to give the titleproduct as a colorless liquid. Purification was by flash chromatographyand vacuum distillation (b.p.=106° C., 1.4 mm of Hg) which afforded thepure product as a colorless liquid (493.8 mg, 60.22%).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 6.0 (br s, 1H), 3.57 (m, 1H), 3.44 (m, 4H),1.32 (m, 1H) 1.14 (d, 6H), 0.94 (m, 2H), 0.7 (m, 2H); MS (EI, M⁺):calculated for C₉H₁₇NO₂ 171.12, found 171.12; IR (CH₂Cl₂) 3299.39,3092.61, 2971.98, 2868.14, 1644.61, 1552.31, 1197.34 cm⁻¹; ¹³CNMR (125MHz, CDCl₃) δ 173.41, 71.76, 66.68, 39.83, 22.10, 14.72, 7.07.

Example 25 Preparation of (±)-trans-2-Phenyl-cyclopropanecarboxylic acid2-isopropoxy-ethyl ester

2-Isopropoxy-ethanol (1.1 eq, 3.04 mmol, 0.32 g, 0.35 ml), pyridine (0.5eq, 1.38 mmol, 0.11 g, 0.11 ml), triethylamine (1.1 eq, 3.04 mmol, 0.31g, 0.43 ml) were taken in a 10 ml round bottom flask and dichloromethane(6 ml) was added. This mixture was cooled to 0° C. and then(±)-trans-2-phenyl-cyclopropanecarbonyl chloride (2.76 mmol, 0.5 g, 0.43ml) was added in a dropwise fashion, maintaining the temperature at 0°C.

A white precipitate was observed after sometime. Stirring was continuedfor 30 minutes at 0° C. The reaction was monitored by thin layerchromatography and then quenched with saturated ammonium chloridesolution. The mixture was then transferred to a separatory funnel,washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5ml), and then with brine (5 ml). The dichloromethane layer was separatedfrom the aqueous layer, dried over anhydrous magnesium sulphate,filtered, and evaporated in vacuo to give the title product as a paleyellowish liquid. Purification was by flash chromatography whichafforded the pure product as a colorless liquid (450.0 mg, 65.0%). Theabove compound is racemic as determined by chiral HPLC (chiralcel OJcolumn) 2% Isopropanol in hexane. UV λ_(max)=278 nm (flow=1 ml/min).

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 7.07-7.27 (m, 5H), 4.22 (m, 2H), 3.61 (m, 3H),2.51 (m, 1H) 1.93 (m, 1H), 1.58 (m, 1H), 1.26 (m, 1H), 1.53 (d, 6H); MS(EI, M⁺): calculated for C₁₅H₂₀O₃ 248.14, found 248.14; IR (CH₂Cl₂)3063.09, 3030.28, 2971.95, 2867.20, 1727.02, 1151.71 cm⁻¹; ¹³CNMR (125MHz, CDCl₃) δ 173.27, 139.92, 128.36, 126.39, 126.10, 72.01, 65.94,64.33, 26.44, 24.17, 22.10, 17.26.

Example 26 Preparation of (±)-trans-2-Phenyl-cyclopropanecarboxylic acid2-ethoxy-ethyl ester

This compound was prepared using the procedure described in Example 25and using the following reagents: 2-ethoxy-ethanol (1.1 eq, 3.05 mmol,0.27 g, 0.30 ml) pyridine (0.5 eq, 1.39 mmol, 0.11 g, 0.11 ml),triethylamine (1.1 eq, 3.05 mmol, 0.31 g, 0.43 ml); and(±)-trans-2-phenyl-cyclopropanecarbonyl chloride (2.77 mmol, 0.5 g, 0.43ml).

The compound was characterized by NMR (¹H and ¹³C), IR and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 7.06-7.28 (m, 5H), 4.24 (m, 2H), 3.62 (m, 2H),3.52 (q, 2H) 2.51 (m, 1H), 1.94 (m, 1H), 1.58 (m, 1H), 1.29 (m, 1H),1.19 (t, 3H); MS (EI, M⁺): calculated for C₁₄H₁₈O₃ 234.12, found 234.12;IR (CH₂Cl₂) 2975.07, 2868.63, 1726.37, 1175.66 cm⁻¹; ¹³CNMR (125 MHz,CDCl₃) δ 173.26, 139.90, 128.37, 126.40, 126.08, 68.36, 66.65, 64.04,26.48, 24.13, 17.35, 15.2

Example 27 Preparation of 1-Phenyl-cyclopropanecarboxylic acid2-ethoxy-ethyl ester

1-Phenyl-cyclopropanecarboxylic acid (0.5 g, 3.1 mmol), was dissolved inthionyl chloride (10 eq, 0.031 mol, 3.68 g, 2.3 ml), and refluxed at 80°C. for 1.5 hours. Then excess of thionyl chloride was evaporated on therotary evaporator which yielded a dark-yellowish liquid(1-phenyl-cyclopropanecarbonyl chloride A), which was then cooled to 0°C., under argon.

2-Ethoxy-ethanol (1.1 eq, 3.41 mmol, 0.31 g, 0.33 ml) and pyridine (1.2eq, 3.41 mmol, 0.27 g, 0.28 ml) was taken in a 25 ml round bottom flaskand dichloromethane (10 ml) was added. This mixture was cooled to 0° C.and then A was added in a dropwise fashion maintaining the temperatureat 0° C. Stirring was continued for 30 minutes at 0° C. The reaction wasmonitored by thin layer chromatography and then quenched with saturatedammonium chloride solution. The mixture was then transferred to aseparatory funnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1hydrochloric acid (2×5 ml), and then with brine (5 ml). Thedichloromethane layer was separated from the aqueous layer, dried overanhydrous magnesium sulphate, filtered, and evaporated in vacuo to givethe title product as a pale yellowish liquid. Purification was by flashchromatography and vacuum distillation (b.p.=93° C., 2.4 mm of Hg),which afforded the pure product as a colorless liquid (437.7 mg, 60.62%)

Characterization was done by NMR (¹H and ¹³C), IR, and massspectroscopy:

¹HNMR (300 MHz, CDCl₃) δ 7.2-7.35 (m, 5H), 4.14 (m, 2H), 3.51 (m, 2H),3.35 (q, 2H) 1.60 (dd, 2H), 1.18 (dd, 2H), 1.1 (t, 3H); MS (EI, M⁺):calculated for C₁₄H₁₈O₃ 234.12, found 234.12; IR (CH₂Cl₂) 2958.04,2837.41, 1676.09, 1600.65, 1288.07 cm⁻¹; ¹³CNMR (125 MHz, CDCl₃) δ174.28, 139.40, 130.41, 127.97, 127.00, 68.11, 66.57, 64.43, 29.19,16.59, 15.23.

Note:

For the compounds of Examples 1 to 27, the solvent system used for flashchromatography was ethyl acetate/hexane, unless otherwise specified.

TABLE 1A Starting Molecular Carbonyl Starting R′- Example CompoundWeight Chloride YH compound  1 MM054

232.28 P* 2-[2-(2- Methoxy- ethoxy)- ethoxy]- ethanol  2 MM055

157.17 B** Methyl ester glycine hydrochloride (Amino Acid)  3 MM056

246.31 B 2-[2-(2- Methoxy- ethoxy)- ethoxy]- ethanol  4 MM057

264.31 P 2-(2- Benzyloxy- ethoxy)- ethanol  5 MM058

157.17 P Methyl ester alanine hydrochloride (Amino Acid)  6 MM059

278.34 B 2-(2- Benzyloxy- ethoxy)- ethanol  7 MM060

244.32 B 2-(2-Butoxy- ethoxy)- ethanol  8 MM061

216.27 B 2-(2-ethoxy- ethoxy)- ethanol  9 MM062

201.26 P 2-(2- dimethylamino- ethoxy)- ethanol 10 MM063

215.29 B 2-(2- dimethylamino- ethoxy)- ethanol 11 MM064

258.35 P 2-(2- hexyloxy- ethoxy)- ethanol 12 MM065

272.39 B 2-(2- hexyloxy- ethoxy)- ethanol 13 MM066

188.23 P 2-(2-methoxy- ethoxy)- ethanol 14 MM067

202.25 B 2-(2-methoxy- ethoxy)- ethanol 15 MM068

158.20 P 2-ethoxy- ethanol 16 MM069

172.23 B 2-ethoxy- ethanol 17 MM070

172.23 P 2-Isopropoxy- ethanol 18 MM071

186.25 B 2-Isopropoxy- ethanol 19 MM072

242.27 P 2-(2-Hydroxy- ethoxy)- ethanol 20 MM073

270.32 B 2-(2-Hydroxy- ethoxy)- ethanol 21 MM074

286.32 P 2-[2-(2- Hydroxy- ethoxy)- ethoxy]- ethanol 22 MM075

314.37 B 2-[2-(2- Hydroxy- ethoxy)- ethoxyl- ethanol 23 MM076

508.60 P N,N,N′,N′ Tetrakis(2- hydroxyethyl) ethyl- enediamine 24 MM077

171.24 P 2-Amino- ethyl isopropyl ether 25 MM078

248.32 trans-2- phenyl- cyclopro- panecar- bonyl chloride 2- Isopropoxy-ethanol 26 MM079

234.29 trans-2- phenyl- cyclopro- panecar- bonyl chloride 2-ethoxy-ethanol 27 MM080

234.29 1-phenyl- cyclo- propane- carbonyl chloride 2-ethoxy- ethanol

The compounds of Table 2B may be prepared using methods within thepurview of one of skill in the art, including using methods similarand/or analogous to those described in Examples 1 to 27 and in theDetailed Description of the Invention and using the appropriate startingmaterials.

Example A Glucose Oxidation Stimulation in Untreated Hearts andMyocardial Cells Treated with Cyclopropanecarboxylic Acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester

Rat hearts were cannulated for isolated working heart 60 minute aerobicperfusions as described in J Pharmacol Exp Ther. 1993; 264:135-144, theentire disclosure of which is incorporated herein by reference.

Male Sprague-Dawley rats (0.3-0.35 kg) were anesthetized withpentobarbital sodium (60 mg/kg IP) and hearts were quickly excised, theaorta was cannulated and a retrograde perfusion at 37° C. was initiatedat a hydrostatic pressure of 60 mm Hg. Hearts were trimmed of excesstissue, and the pulmonary artery and the opening to the left atrium werethen cannulated. After 15 min of Langendorff perfusion, hearts wereswitched to the working mode by clamping the aortic inflow line from theLangendorff reservoir and opening the left atrial inflow line. Theperfusate was delivered from an oxygenator into the left atrium at aconstant preload pressure of 11 mm Hg. Perfusate was ejected fromspontaneously beating hearts into a compliance chamber (containing 1 mlof air) and into the aortic outflow line. The afterload was set at ahydrostatic pressure of 80 mm Hg. All working hearts were perfused withKrebs'-Henseleit solution containing calcium 2.5 mmol/L, glucose 5.5mmol/L, 3% bovine serum albumin (fatty acid free, initial fractionationby heat shock, Sigma), and with 1.2 mmol/L palmitate. Palmitate wasbound to the albumin as described in J Bio Chem. 1992; 267:3825-3831,the entire disclosure of which is incorporated herein by reference.

The perfusate was recirculated, and pH was adjusted to 7.4 by bubblingwith a mixture containing 95% O₂ and 5% CO₂.

Spontaneously beating hearts were used in all perfusions. Heart rate andaortic pressure were measured with a Biopac Systems Inc. blood pressuretransducer connected to the aortic outflow line. Cardiac output andaortic flow were measured with Transonic T206 ultrasonic flow probes inthe preload and afterload lines, respectively. Coronary flow wascalculated as the difference between cardiac output and aortic flow.Cardiac work was calculated as the product of systolic pressure andcardiac output.

Measurement of Glucose Oxidation: Glucose oxidation was measuredsimultaneously by perfusing hearts with [U-¹⁴C] glucose according to theprocedures discussed in Saddik M, et al., J Bio Chem. 1992;267:3825-3831. The entire disclosure of this reference is incorporatedherein by reference. The total myocardial ¹⁴CO₂ production wasdetermined at 10-min intervals from the 60-min aerobic period. Glucoseoxidation rates were determined by quantitative measurement of ¹⁴CO₂production as described in Barbour R L, et al., Biochemistry. 1984;1923:6503-6062. The entire disclosure of this reference is incorporatedherein by reference. ¹⁴CO₂ production for the control group werecompared with the ¹⁴CO₂ production for the group treated withcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. Results are shown on FIG. 1 and TABLE 2A.

Example B (1) Glucose Oxidation Stimulation in Untreated Hearts andMyocardial Cells Treated with Cyclobutanecarboxylic Acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester

The procedure of Example A for was followed except thatcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl esterin 1 μM, 10 μM, 100 μM and 1000 μM amounts was added to the buffer inplace of the cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results are illustratedin FIG. 2 and TABLE 2A.

(2) Glucose Oxidation Stimulation in Untreated Hearts and MyocardialCells Treated with Cyclopropanecarboxylic Acid, 2-isopropoxy ethyl ester

The procedure of Example A was followed except thatcyclopropanecarboxylic acid, 2-isopropoxy-ethyl ester in 1 μM, 10 μM,100 μM and 1000 μM amounts was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. The results are illustrated in FIG. 3 and TABLE 2A.

(3) Glucose Oxidation Stimulation in Untreated Hearts and MyocardialCells Treated with Various Cyclopropanecarboxylic Acid andCyclobutanecarboxylic Acid Derivatives

The procedure of Example A was followed except that variouscyclobutanecarboxylic acid derivatives, cyclopropanecarboxylic acidderivatives and cyclobutanecarboxylic acid in the amounts of 100 μM or1000 μM was added to the buffer in place of the cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results areillustrated in TABLE 2A and TABLE 2B.

(4) Glucose Oxidation Stimulation in Untreated Hearts and MyocardialCells Treated with Cyclopropanecarboxylic Acid

The procedure of Example A was followed except thatcyclobutanecarboxylic acid the amounts of 0.001 μM, 0.01 μM, 01 μM, 1μM, 10 μM, and 100 μM was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. The results are illustrated in FIG. 4.

TABLE 2A Glucose Compound Screening Oxida- of Concentra- tion Exampletion (% above No. Compound (μM) control)  1 MM054

100 102%  2 MM055

1000 μM 58%  3 MM056

100 μM 54%  4 MM057

100 μM 104%  5 MM058

1000 μM 40%  6 MM059

100 μM 68%  7 MM060

100 μM 65%  8 MM061

Not screened  9 MM062

100 μM 77% 10 MM063

100 μM 41% 11 MM064

100 μM 83% 12 MM065

100 μM 0% 13 MM066

100 μM 20% 14 MM067

100 μM 50% 15 MM068

100 μM 416% 16 MM069

100 μM 162% 17 MM070

100 μM 208% 18 MM071

100 μM 97% 19 MM072

100 μM 97% 20 MM073

100 μM 243% 21 MM074

100 μM 228% 22 MM075

100 μM 184% 23 MM076

100 μM 274% 24 MM077

100 μM 217% 25 MM078

100 μM 200% 26 MM079

not screened 27 MM080

not screened

TABLE 2B Screening Glucose Concentra- Oxidation Molecular tion (% aboveNo. Compound Weight (μM) control) 27 MM080

234.29 100 μM 148% 28 MM081

172.22 100 μM 121% 29 MM082

214.30 100 μM 110% 30 MM083

144.17 100 μM 197% 31 MM084

274.31 100 μM 197% 32 MM085

172.22 100 μM 150% 33 MM086

241.11 100 μM 117% 34 MM087

336.42 100 μM 112% 35 MM088

520.53 100 μM 205% 36 MM089

211.28 100 μM 202% 37 MM090

174.22 100 μM 251% 38 MM091

187.26 100 μM 176% 39 MM092

199.25 100 μM 233% 40 MM093

214.26 100 μM 260% 41 MM094

234.25 100 μM 389% 42 MM095

182.24 100 μM 314% 43 MM096

264.32 100 μM 93% 44 MM097

308.37 100 μM 125% 45 MM098

198.22 100 μM 358% 46 MM099

350.41 100 μM 93%

Example C Pyruvate Dehydrogenase Kinase (PDHK) Inhibition Assay

This assay is based on the method of Jackson, et al. Biochem J.334:203-711 (1998). It is an adaptation of a pyruvate dehydrogenase(PDH) assay in which measures NADH (@ 340 nm) formed when pyruvate isconverted to acetyl CoA. PDHK activity is measured as the amount of PDHactivity remaining after ATP activation of PDHK, which in turndeactivates PDH. Pyruvate dehydrogenase enzyme complex (PDC) ispurchased from Sigma. It contains intrinsic pyruvate dehydrogenasekinase (PDK) activity.

1) PDC is pre-incubated in Buffer A (40 mM MOPS, pH 7.2, 0.5 mM EDTA, 30mM KCl. 1.5 mM MgCl₂, 0.25 mM acetyl CoA, 0.05 mM NADH, 2 mMdithiothreitol, 10 mM NaF) for 40 minutes at 37° C. This step increasestotal PDH activity.

2) The PDK reaction is started by adding 45.5 μl of pre-incubated enzyme(step 1) to 54.5 μl of PDK reaction solution (1.8× buffer A, 55 μM ADP±100 μM ATP, ±drug). The reaction is run for 3 minutes@37° C. and thenstopped by adding 10 μl of Stop solution (55 mM ADP, 55 mM pyruvate).

3) PDH activity is then assayed by adding 90 μl of Buffer B (120 mMTris-HCl, pH 7.8, 0.61 mM EDTA, 0.73 mM MgCl₂, 2.2 mM cocarboxylase, 11mM β-mercaptoethanol, 2.2 mM NAD, 2.2 mM pyruvate, 1.1 mM coenzyme A)and read at 340 nm kinetically for 2 minutes.

4) Drug inhibition levels are compared to the control reaction (no addeddrug) which is considered to have 100% kinase activity.

(a) Pyruvate Dehydrogenase Kinase Assay Solutions

Buffer A (10×)

-   -   40 ml 1 M MOPS    -   1 ml of 0.5 M EDTA    -   10 ml of 3 M KCl    -   10 ml of 150 ml MgCl₂    -   10 ml of 200 mM DTT

This buffer is made and kept at 4° C. On the day of the assay 7.1 ml ofBuffer A (10×) is added to 1 ml of 2.5 mM acetyl CoA. 1 ml of 0.5 mMNADH, and 0.9 ml water added make Buffer A (1×)

Freshly made solutions:

-   -   2.5 mM Acetyl CoA    -   0.5 mM NADH    -   550 mM ADP    -   1 mM ATP    -   22 mM cocarboxylase    -   22 mM NAD    -   11 mM Coenzyme A

(b) PDK Reaction Solution

Solution Volume Buffer A (10X) 50 μl 550 μM ADP 27.8 μl 1 mM ATP 27.8 μl(0) Drug (or DMSO) 55.5 μl H₂O 117 μl Total Volume 277.8 μl ( )indicates volumes for kinase negative reactions used to determine totalPDH activity.

(c) PDK Stop Solution

Solution Volume 550 mM ADP  150 μl 550 mM pyruvate  150 μl DD H₂O 1200μl Total Volume 1500 μl

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

1-90. (canceled)
 91. A method for increasing glucose utilization in acell, tissue or organ of a warm blooded animal which comprises treatingsaid cell, tissue or organ with a glucose utilization effective amountof a compound selected from the group consisting of a prodrug of

cyclopropane thiocarbonyl CoA or a thioester of cyclopropanecarbothionic acid.
 92. A method for increasing glucose utilization in acell, tissue or organ of a warm blooded animal which comprises treatingsaid cell, tissue or organ with a glucose utilization effective amountof a compound which forms a CoA ester in vivo wherein said compound isrepresented by Formula (I):

wherein (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,optionally substituted aralkyl or optionally substituted aralkenyl, (b)Cyc is C₃ or C₄ cycloalkyl; (c) p is an integer from 0 to 4; (d) m is 1or 2; (e) Y is O, S, or NR; (f) X is O, S, NR, or CR³R⁴; (g) R is H,alkyl, aryl, or

where i is an integer from 2 to 4; (h) Z is H, alkyl, heterocycle alkyl,cycloalkyl, aryl or optionally substituted C₁-C₆ alkylcarbonyl or

when X is NR and R is

or when X is NR, R and Z may be taken together with N to form anitrogen-containing heterocyclic ring; (i) R¹ is H, alkyl or aryl; (j)R² is H, alkyl, aryl or ═O; (k) R³ and R⁴ are, independently, H, alkylor aryl; or when X is CR³R⁴ then R³ and R⁴, taken together with thecarbon atom, may form a heterocyclic ring; and (l) n is an integer from0 to 10, or a pharmaceutically acceptable salt, ester or prodrugthereof.
 93. (canceled)
 94. A method for treatment of physiologicalconditions or disorders treatable by increasing glucose utilizationcomprising administering to a patient in need of such treatment anamount of a PDHK inhibitor effective to increase glucose utilization.95. The method of claim 94 wherein said PDHK inhibitor comprises acompound which forms a CoA ester in vivo, wherein said compound isrepresented by Formula (I):

wherein (a) W is C₁-C₆ alkyl, halogen, optionally substituted aryl,optionally substituted aralkyl or optionally substituted aralkenyl; (b)Cyc is C₃ or C₄ cycloalkyl, (c) p is an integer from 0 to 4; (d) m is 1or 2; (e) Y is O, S, or NR; (f) X is O, S, NR, or CR³R⁴; (g) R is H,alkyl, aryl, or

where i is an integer from 2 to 4; (h) Z is H, alkyl, heterocycle alkyl,cycloalkyl, aryl or optionally substituted C₁-C₆ alkylcarbonyl or

when X is NR and R is

or when X is NR, R and Z may be taken together with N to form anitrogen-containing heterocyclic ring; (i) R¹ is H, alkyl or aryl; (i)R² is H, alkyl, aryl or ═O; (k) R³ and R⁴ are, independently, H, alkylor aryl; or when X is CR³R⁴ then R³ and R⁴, taken together with thecarbon atom, may form a heterocyclic ring; and (l) n is an integer from0 to 10, or a pharmaceutically acceptable salt, ester or prodrugthereof.
 96. (canceled)
 97. The method of claim 92, wherein saidcompound is selected from the group consisting of:1-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester; 2,2,3,3,tetramethyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;trans-2-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;2,2-dichloro-1-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;(1S,2S)-2-phenyl-styryl-cyclopropanecarboxylic acid, 2-ethoxy-ethylester; 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid, 2-ethoxy-ethylester; 1-phenyl-cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;1-(1-phenyl-1-cyclopropanecarboxylicacid)-2-(1-phenyl-cyclopropanecarbonyloxy)-ethyl ester;cyclopropane-carboxylic acid, 2-cyclopropanecarbonyloxy-ethyl ester;cyclopropane-1,1-dicarboxylic acid, bis-(2-ethoxy-ethyl) ester;cyclopropanecarboxylic acid, 2-methoxy-ethyl ester;cyclopropanecarboxylic acid, 2-(4-methyl-thiazol-5-yl)-ethyl ester;cyclopropanecarboxylic acid-2-morpholin-4-yl-ethyl ester;cyclopropanecarboxylic acid, 5-ethyl-[1,3]-dioxan-5-ylmethyl ester;cyclopropanecarboxylic acid, 2,3-dihydro-benzo(1,4)-dioxin-2-ylmethylester; cyclopropanecarbonylsulfanyl-acetic acid methyl ester;cyclopropanecarbothioic acid, S-(2-acetylamino-ethyl) ester;cyclopropanecarbothioic acid, S-furan-2-ylmethyl ester; and1,2,3,5,6-penta-O-(cyclopropanecarbonyl)-D-glucopyranose.
 98. The methodof claim 95, wherein said compound is selected from the group consistingof: 1-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester; 2,2,3,3,tetramethyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;trans-2-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;2,2-dichloro-1-methyl-cyclopropanecarboxylic acid, 2-ethoxy-ethyl ester;(1S,2S)-2-phenyl-styryl-cyclopropanecarboxylic acid, 2-ethoxy-ethylester; 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid, 2-ethoxy-ethylester; 1-phenyl-cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;1-(1-phenyl-1-cyclopropanecarboxylicacid)-2-(1-phenyl-cyclopropanecarbonyloxy)-ethyl ester;cyclopropane-carboxylic acid, 2-cyclopropanecarbonyloxy-ethyl ester;cyclopropane-1,1-dicarboxylic acid, bis-(2-ethoxy-ethyl) ester;cyclopropanecarboxylic acid, 2-methoxy-ethyl ester;cyclopropanecarboxylic acid, 2-(4-methyl-thiazol-5-yl)-ethyl ester;cyclopropanecarboxylic acid-2-morpholin-4-yl-ethyl ester;cyclopropanecarboxylic acid, 5-ethyl-[1,3]-dioxan-5-ylmethyl ester;cyclopropanecarboxylic acid, 2,3-dihydro-benzo(1,4)-dioxin-2-ylmethylester; cyclopropanecarbonylsulfanyl-acetic acid methyl ester;cyclopropanecarbothioic acid, S-(2-acetylamino-ethyl) ester;cyclopropanecarbothioic acid, S-furan-2-ylmethyl ester; and1,2,3,5,6-penta-O-(cyclopropanecarbonyl)-D-glucopyranose.